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When severe pain and stimulation of the pituitary-adrenal-gonadal axis goes unabated for a considerable time period, exhaustion of some adrenal compounds may develop and, left untreated, may pose a combination of a serious, life-threatening condition, a vegetative state with incapacitation, mental disturbance, and a house- or bed-bound state.

In 2005, I published an article in these pages entitled “Hormone Treatment of Chronic and Intractable Pain.” At that time, I suggested that testosterone and perhaps other hormones would join corticosteroids in pain treatment. Since that report, corticosteroids—due to their numerous pain-related functions—continue to be a mainstay in pain treatment for epidural and paraspinal interventions, intralesional injections, and numerous topical and oral applications.1-3 Testosterone replacement in males who require regular opioid dosing has become a standard practice.4-6

The major hormone developments since 2005 are two-fold. First, it is now clear that severe pain, per se, may produce some hormonal deficiencies in the pituitary-adrenal-gonadal axis (here-after “axis”) that may need replacement7,8 (see Figure 1). Opioid administration may also cause various hormonal deficiencies of which testosterone is the most notable. Testosterone replacement is now routine in males and starting to be used in females.9,10 Occasionally, opioid administration may require other hormone replacement.3 The second major development is the use of hormonal compounds and analogues for healing of injured, degenerated or painful tissue sites. Early clinical reports indicate that human chorionic gonadotropin (HCG), human growth hormone (HGH), and some intermediaries of the steroidogenic pathway such as progesterone, androstenedione, and dehydroepiandrosterone (DHEA) may have clinical merit.12-15

It essentially appears that a subspecialty or body of knowledge involving pain endocrinology is emerging. In fact, pain management is beginning to learn aspects about the endocrine system that has not been a necessary area of interest or pursuit in classic endocrinology, gynecology, or urology. This article attempts to give a “point-in-time” endocrine update that is specifically geared to the pain practitioner.

Table 1. Sympathetic Signs Caused By Catecholamine Release

Tachycardia (high pulse rate)

Hypertension

Dilated pupil (mydriasis)

Cold extremities

Gooseflesh

Hyperreflexia

Table 2. Vegetative State Induced by Hormone Disturbances

Incapacitated

Pain is constant

Insomnia

Muscle wasting

Stares/looks straight ahead

Speaks softly and slowly

Poor responder to questions and history

Walks slowly

May appear apathetic, unmotivated, or uncooperative

Poor function at home and work

House-, bed-, or couch-bound

Depressed, lethargic

The Critical Knowledge About Hormones

Every pain practitioner must have a basic understanding of how severe pain, acute and chronic, affects the axis. This knowledge is fundamental to knowing if pain is severe enough to require aggressive medical intervention. It is the disturbance of the axis that fundamentally incapacitates a chronic pain patient and puts them in a vegetative, non-functional, bed- or house-bound state.7

Chronic, severe, uncontrolled pain will initially over-stimulate the axis to cause high serum levels of glucocorticoids (e.g., cortisol, pregnenolone), and catecholamines (e.g., adrenaline, noradrenaline) and this sequence of events is illustrated in Figure 1. If over-stimulation continues, adrenal and gonadal exhaustion will occur resulting in low serum glucocorticoids and catecholamines, and possibly other compounds in the steroidogenic pathway. The steroidogenic pathway8,16 in the adrenal and gonads is illustrated in Figure 2. I recommend these figures be kept in the office for ready reference and education of patients.

Phase One: Overstimulation of the Pituitary-Adrenal-Gonadal Axis

Severe pain is a potent—if not the most potent—stressor to the axis. In severe acute or chronic pain, the axis will be over-stimulated resulting in release of catecholamines (adrenalin and noradrenaline) from the adrenal medulla. Clinically, they give a classic sympathetic picture that includes tachycardia, pupil dilation (mydiacis), and cold extremities (see Table 1). The adrenal cortex is activated by adrenocorticotrophin hormone (ACTH) from the pituitary. Glucocorticoids, particularly cortisol and pregnenolone, are released and can be measured in the serum. Glucocorticoids may contribute to hypertension caused by catecholamine release. A short-term duration of serum glucocorticoid (e.g. cortisol) elevation produces no lasting effects and may positively contribute to the immune and healing response. Long-term high serum cortisol levels, however, produce all the destructive effects caused by classic Cushing’s Disease (Hyperadrenalism).3 The most destructive effects in severe chronic pain patients that have been observed first-hand by the author are osteoporosis, dental erosion, obesity, hyperglycemia, hyperlipidemia and poor pain control. Of particular note has been progressive spine degeneration often involving the entire spine. Excess serum catecholamines produce musculoskeletal pain and are probably the cause of the generic label “myofascial pain syndrome.” For example, you may have damage to the lumbar spine, hip, or foot with severe pain and develop muscular pain in the chest and shoulder muscles. There is an old myth that only acute pain (i.e., post-trauma or surgery) causes overstimulation of the axis with tachycardia and/or hypertension. All severe pain—acute, chronic, persistent, or intractable of any duration—can cause overstimulation of the axis, and the malady does not stop until medication, usually opioids, is administered.

Phase Two: Exhaustion of the Pituitary-Adrenal-Gonadal Axis

If pain is severe and uncontrolled for a long time period, overstimulation of the axis continues unabated. At some point adrenal reserves exhaust or deplete.16 When this occurs, serum pregnenolone and cortisol may drop to dangerously low levels. The drop may be to levels that are usually not compatible with life (e.g., cortisol under 2 ug/dl or pregnenolone under 5ng/dl). It is my belief that adrenal exhaustion is responsible for many, if not most, of the sudden unexplained deaths in chronic pain patients. At this time, it is unclear as to how much pituitary and gonadal exhaustion may occur with severe uncontrolled pain; data is only available for adrenal exhaustion. There is, however, a very high prevalence of pituitary tumors and deficiencies in chronic pain patients and some serum deficiencies of androgens and estrogens may be observed in severe, chronic pain patients.

25. Horton R and Tail JF. Androstenedione production and interconversion rates measured in peripheral blood and studies on the possible site of its conversion to testosterone. J Clin Invest. 1966. 45: 301-313.

26. Mahesh VB and Greenblatt RB. The in vivo conversion of dehydroepiandrosterone and androstenedione to testosterone in the human. Acta Endocrin. 1962. 41: 400-405.

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